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Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres, cycloaddition reactions have featured in numerous total syntheses and are a key component in the education of chemistry students. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp manner. Despite the ability of cycloadditions to introduce multiple carbon sp centres in a single step, they are less used. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.

Alkyl boronic acids and esters play an important role in the synthesis of C(sp 3 ) rich medicines, agrochemicals, and other materials. This work describes a new type of transition-metal free mediated transformation to enable the construction of C(sp 3)-rich, and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry. The strategic significance of this approach, with alkyl boronic acid as a linchpin, is demonstrated through various downstream functionalizations of the alkyl boron compounds. This two-step concurrent cross-coupling approach, resembling formal and flexible alkyl-alkyl couplings, provides a general entry to previously synthetically challenging high Fsp 3 -containing drug-like scaffolds.File list (2) download file view on ChemRxiv Manuscript--Chemrxiv modified.pdf (794.17 KiB) download file view on ChemRxiv chemrxiv SI.pdf (14.12 MiB)

Despite the tremendous utilities of metal-mediated cross-couplings in modern organic chemistry, coupling reactions involving nitrogenous heteroarenes remain a challenging undertaking -coordination of Lewis basic atoms into metal centers often necessitate elevated temperature, high catalyst loading, etc. Herein, we report a sulfur (IV) mediated crosscoupling amendable for the efficient synthesis of heteroaromatic substrates. Addition of heteroaryl nucleophiles to a simple, readily-accessible alkyl sulfinyl (IV) chloride allows formation of a trigonal bipyramidal sulfurane intermediate. Reductive elimination therefrom provides bis-heteroaryl products in a practical and efficient fashion.

A prevalent feature of Strongyloides stercoralis is a life-long and potentially lethal infection that is due to the nematode parasite’s ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite’s nuclear receptor, Ss-DAF-12, in governing infection. We identified Δ7-DA as the endogenous Ss-DAF-12 ligand and elucidated the hormone’s biosynthetic pathway. Genetic loss of function of the ligand’s rate-limiting enzyme demonstrated that Δ7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for the development of infectious larvae. Availability of the ligand permits Ss-DAF-12 to function as an on/off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclinical model of hyperinfection, pharmacologic activation of DAF-12 suppressed autoinfection and markedly reduced lethality. Moreover, when Δ7-DA was administered with ivermectin, the current but limited drug of choice for treating strongyloidiasis, the combinatorial effects of the two drugs resulted in a near cure of the disease.

Alkyl boronic acids and esters play an important role in the synthesis of C(sp³) rich medicines, agrochemicals, and other materials. This work describes a new type of transition-metal free mediated transformation to enable the construction of C(sp³)-rich, and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry. The strategic significance of this approach, with alkyl boronic acid as a linchpin, is demonstrated through various downstream functionalizations of the alkyl boron compounds. This two-step concurrent cross-coupling approach, resembling formal and flexible alkyl-alkyl couplings, provides a general entry to previously synthetically challenging high Fsp³-containing drug-like scaffolds.

<p>Bicyclic hydrocarbons, bicyclo[1.1.1]pentanes (BCPs) in particular, play an emerging role as saturated bioisosteres in pharmaceutical, agrochemical, and material chemistry. Taking advantage of strain release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. This work describes a novel approach to accessing multi-substituted BCPs via a new type of intramolecular cyclization. In addition to the C1, C3-disubstituted BCPs, this method also enables the construction of yet underexplored tri-substituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this cyclization is examined through synthesis of a variety of caged bicyclic molecules, ranging from [1.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead Bpin resulted from the cyclization is demonstrated via several downstream functionalizations, highlighting the ability of this approach for programmed and divergent synthesis of multi-substituted bicyclic hydrocarbons.<br></p>

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